Skip Navigation LinksHome > January 2012 - Volume 15 - Issue 1 > Cytokines: muscle protein and amino acid metabolism
Current Opinion in Clinical Nutrition & Metabolic Care:
doi: 10.1097/MCO.0b013e32834e6ea2
PROTEIN, AMINO ACID METABOLISM AND THERAPY: Edited by Olav Rooyackers and John Brosnan

Cytokines: muscle protein and amino acid metabolism

van Hall, Gerrita,b

Free Access
Article Outline
Collapse Box

Author Information

aClinical Metabolomics Core Facility, Rigshospitalet

bDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

Correspondence to Gerrit van Hall, Clinical Metabolomics Core Facility, Rigshospitalet, Section 7651, 9 Blegdamsvej, DK-2100, Copenhagen, Denmark. Tel: +45 3545 7595; e-mail: gvanhall@regionh.rh.dk

Collapse Box

Abstract

Purpose of review: This review highlights the role of cytokines, in particular tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), in relation to the nature of human in-vivo muscle wasting in disease.

Recent findings: Infusion of human TNF-α and IL-6 in healthy individuals, acutely raises TNF-α and IL-6 to moderate levels, has only identified IL-6 as a potent cytokine, decreasing systemic amino acid levels and muscle protein metabolism. The marked decrease in circulatory and muscle amino acid concentrations was observed with a concomitant reduction in both the rates of muscle protein synthesis and breakdown, that is, reduced turnover with a minor increase in net muscle degradation. Very similar observations have been made in models of acute inflammation, induced by high-dose endotoxin injection. However, these changes were suggested not to be attributed to a direct effect of IL-6 on the regulation of muscle protein metabolism but indirectly via IL-6 reducing amino acid availability.

Summary: Recent studies suggest that the best described cytokines TNF-α and IL-6 are unlikely to be the major direct mediators of muscle protein loss in inflammatory diseases. However, these cytokines can initiate important changes in secondary mediators and/or clinical complications that need correction therapies causing muscle wasting. Moreover, the general view from animal work is that in muscle wasting the rate of muscle protein synthesis is decreased and the rate of breakdown is increased. However, this does not seem applicable for inflammatory diseases or human models of sepsis, in which the enhanced imbalance between these two processes is observed within an enhanced, normal or reduced muscle protein turnover.

Back to Top | Article Outline

INTRODUCTION

Severe loss of muscle mass and hypercytokinaemia are hallmarks in critical ill patients with sepsis, multiple organ failure, severe trauma and severe burn injuries, and also in chronic inflammation disorders such as rheumatoid arthritis, AIDS, cancer, chronic heart failure and chronic obstructive pulmonary disease. In these conditions, muscle wasting is associated with chronic elevations in circulating proinflammatory cytokines, in particular tumour necrosis factor alpha (TNF-α), that in the 1980s was identified as cachectin because it was suggested that TNF-α was a direct cause of lean body mass erosion and pronounced impairment in the muscle protein balance. More recently, interleukin-6 (IL-6) has also been identified to play a major role in muscle wasting. Although the clinical features of the muscle wasting process are readily apparent, its pathogenesis is complex. Obviously, muscle atrophy is caused by an imbalance between the rates of muscle protein synthesis and breakdown but not, necessarily, by a decrease in the rate of synthesis and increase in breakdown. To date, it is not clear how these processes are affected in human disease and the role of cytokines herein. This review will give an update of the role of the cytokines TNF-α and IL-6 in relation to the nature of human in-vivo muscle wasting.

Back to Top | Article Outline

INFLAMMATION AND MUSCLE PROTEIN METABOLISM

Box 1
Box 1
Image Tools

Animal models of inflammation indicate that the rate of muscle protein synthesis is reduced, whereas breakdown is increased and that this opposing response facilitates the profound and fast skeletal muscle loss [1–3]. These findings are supported by similar observations in the model of sepsis [4,5], endotoxin injection or infusion, with elevated transcription and signalling events associated with a suppression of muscle synthesis and an increase in proteolysis [6].

Numerous clinical studies report a substantial loss of muscle mass in a variety of diseases with low grade or severe inflammation. However, relatively few studies have investigated how in these diseases the rate of muscle protein synthesis and breakdown are affected (Fig. 1). The best studied patients are those with severe burn injuries. They are characterized by a substantial increase in both the rate of muscle protein synthesis [7,8] and breakdown [7], albeit breakdown is far more increased than synthesis. Critically ill patients have similar muscle protein synthesis [9,10▪▪] but an enhanced breakdown [10▪▪], whereas cachectic cancer patients with chronic low-grade inflammation [11–14] have a decreased muscle protein synthesis and breakdown [11–14], as also seen in the human model for acute sepsis, induced by endotoxin injection [15,16,17▪▪]. Of note is that the increased, unchanged and decreased muscle protein turnover in the various diseases is accompanied by an increased, unchanged and decreased skeletal muscle and blood amino acid concentration, respectively. The differences in findings between rat and clinical studies and the difference between diseases prevent a consistent view on how inflammation affects skeletal muscle protein synthesis and breakdown and hence the role of hypercytokinaemia herein.

Figure 1
Figure 1
Image Tools
Back to Top | Article Outline

CYTOKINES AND MUSCLE PROTEIN METABOLISM

Most information on the role of TNF-α in skeletal muscle protein metabolism originates from C2C12 primary myotube incubations and in-situ and in-vivo animal studies, with usually little or no information on TNF-α levels achieved and changes in other cytokines or catabolic hormones. Results from experiments using primary myotube incubations with addition of TNF-α are contradicting. Li and Reid [18] observed an increased degradation of myosin and a reduction in total protein. However, also an increase in protein content and fractional synthetic rate (FSR) by enhancing protein translation is reported [19,20]. Alvarez et al.[19] suggested that these effects were mediated by IL-6, as addition of anti-IL-6 completely abolished the effect of TNF-α on protein synthesis. Williamson et al.[21] was unable to show an effect of TNF-α on protein synthesis but TNF-α abolished the insulin-mediated increase in protein synthesis. In-situ and in-vivo rat studies with acute or chronic TNF-α treatment are equally contradicting. Addition of TNF-α to incubated rat skeletal muscle caused a decrease in muscle protein synthesis [22], no change [23], or an increased proteolysis [23]. Twenty four hours of TNF-α infusion in rats reduced the muscle protein synthesis and was accompanied by a suppression of translation initiation [1]. Goodman [24] observed an increased muscle proteolysis in TNF-α-treated rats for 8 h. However, TNF-α failed to affect proteolysis in the TNF-α-incubated rat muscles, suggesting that the increased proteolysis was not directly caused by TNF-α but mediated in an indirect manner. Chronic elevation of TNF-α for 7–8 days has reported to increase both rat skeletal muscle synthesis and breakdown, and an increased net muscle loss [25]. Another study observed a similar net muscle loss in TNF-α treated as compared to control animals [26]. However, when controlled for the reduced dietary intake induced by TNF-α treatment, the pair-fed group had similar loss of muscle mass suggesting that the TNF-α effect was caused by dietary deficiency. The above-mentioned TNF-α treatment studies in myotubes and rat do not provide a conclusive view of the role of TNF-α on skeletal muscle protein metabolism, even more so, as information on TNF-α concentrations and changes in other cytokines and catabolic hormones are lacking. Nonetheless, overall it seems that TNF-α per se does not increase muscle protein loss.

In cancer patients, isolated limb perfusion with recombinant human (rh)TNF-α did not affect the net release of essential amino acids, suggesting that muscle net protein degradation was unaltered [27]. Systemic infusion of rhTNF-α in cancer patients at dosages that caused severe adverse effects caused an increase in the forearm release of gluconeogenic but not in essential amino acids, suggesting no or at best a very limited effect of TNF-α on skeletal muscle net degradation [28]. Of note is that in spite of the increase in muscle amino acid release, the plasma amino acid concentration decreased with TNF-α infusion suggesting a surge for amino acids by other tissues similarly seen within hours of endotoxin injection [15,16,17▪▪] or rhIL-6 infusion [29] in healthy individuals. The effects of TNF-α on muscle protein metabolism has only been determined in healthy young individuals over 4 h of rhTNF-α infusion at rates raising circulating levels from ∼0.7 to ∼17 pg/ml but not causing adverse effects and apparent changes in major anabolic and catabolic hormones [30]. The acute increase in TNF-α did not cause a measureable change in net muscle degradation nor muscle protein FSR, synthesis and breakdown rates. The achieved TNF-α concentration is similar or higher as seen in chronic low inflammatory diseases, such as cachectic cancer and heart failure, and rheumatoid arthritis. Therefore, it cannot be excluded that the fast muscle wasting seen in sepsis is caused by the much higher chronic TNF-α levels. However, under those conditions other cytokines and catabolic hormones are also greatly elevated. Moreover, it has been suggested that the effect of TNF-α on skeletal muscle loss is mediated by glucocorticoids or that TNF-α and glucocorticoids interact cooperatively [31]. Indirect data exist on the potential involvement of TNF-α in muscle loss from anti-TNF-α therapies in sepsis and cachectic rheumatoid patients. Anti-TNF-α given as a single bolus within 12 h after the onset of sepsis did not affect body protein content as compared to nontreated patients over the following 3 weeks. However, treatment did not alter the overall and overwhelming pattern of cytokine activation either, possibly because the TNF-α levels rebounded quickly [32]. Chronic anti-TNF-α therapy over 12–24 weeks in patients with cachectic rheumatoid arthritis did lower TNF-α levels; however, no changes in body composition (including lean body mass) were found [33]. Finally, in chronic heart failure circulating TNF-α levels did not relate with diminished muscle synthesis response towards hyperinsulinaemia–hyperaminoacidaemia [34▪]. Therefore, little evidence exists from cell culture, animal and clinical investigations that TNF-α per se, in a direct manner, is responsible for an enhanced muscle loss or affecting muscle protein synthesis and breakdown.

Back to Top | Article Outline

INTERLEUKIN-6

Addition of IL-6 to primary myotubes has been shown to increase protein FSR [19], whereas rat and mouse muscles incubated in the presence of IL-6 had an unchanged muscle protein breakdown [35,36]. Rat skeletal muscle protein breakdown pathways were not acutely affected by intravenous injection of IL-6, as demonstrated by a lack of effect on ubiquitin gene expression or cathepsin activity [37]. However, chronic elevation of IL-6 in IL-6 transgenic mice caused atrophy in gastrocnemius muscles [38] that could be blocked by treatment with antimouse IL-6 receptor antibody. Moreover, a genetic mouse model of colorectal cancer and cachectia that showed muscle atrophy in type IIB but not type IIA fibres demonstrated that atrophy was overcome when IL-6 was lacking [39]. The aforementioned studies do not bring forward a uniform view on the role of IL-6 in muscle protein metabolism.

In humans, the role of IL-6 on muscle protein metabolism has been studied via a 3-h infusion of rhIL-6 in healthy young individuals resulting in IL-6 concentrations of about 140 pg/ml [29]. A substantial decrease in both muscle protein synthesis and breakdown was observed with only a small increase in the muscle net proteolysis. The achieved circulating IL-6 concentration was quite higher as compared to the TNF-α levels with a similar set-up that did not affect muscle protein metabolism [30]. However, as the response of an endotoxin challenge or sepsis is several fold higher in IL-6 than TNF-α, the ratio of IL-6 to TNF-α seems physiologically comparable between the studies. The decrease in muscle protein turnover during rhIL-6 infusion is similar to those seen with endotoxin injection [15,16,17▪▪]. In addition, cachectic cancer patients had also reduced muscle protein turnover [11–14]. Therefore, it is tempting to argue that IL-6 and not TNF-α is causing the muscle loss seen in many diseases. However, it was speculated that the remarkable decrease in muscle protein turnover and a minor increase in net muscle loss with rhIL-6 infusion was caused by the substantially reduced amino acid availability and not IL-6 per se [29] as argued similarly for endotoxin injection [17▪▪]. Yet, IL-6 must have a profound effect on increased amino acid utilization in tissues other than skeletal muscle [15], and when not counteracted by protein or amino acid intake, it can cause muscle protein turnover to be decreased and muscle loss enhanced. Therefore, IL-6 per se does not seem to affect human skeletal muscle protein synthesis and breakdown. However, IL-6 profoundly enhances amino acid requirements by other tissues, either for energy requirements or increased protein synthesis leading to reduced systemic amino acid concentration causing skeletal muscle synthesis to decrease followed by breakdown. Future studies on the role of IL-6 on amino acid and protein metabolism should address the effect of amino acid supplementation to prevent hypoaminoacidaemia, as it is a common practice during a hyperinsulinaemic clamp to prevent a substantial decrease in blood amino acids. Systemic insulin administration in the absence of exogenous amino acids report no or a small increase in muscle protein synthesis with a reduced breakdown, whereas those studies that prevent reduced amino acid levels via local insulin infusion or exogenous amino acids administration report a substantial increase in muscle protein synthesis and a further reduction in breakdown [40▪].

Back to Top | Article Outline

DISCUSSION

The general view is that the marked imbalance between muscle protein synthesis and breakdown in severe illness, and the role of cytokine herein, involves a decreased rate of muscle protein synthesis and an increased rate of muscle protein breakdown. Whereas this view seems supported by animal work, the clinical studies do not support it. None of the clinical studies show a divergent response of muscle protein synthesis decreasing and breakdown increasing in spite of the differences in muscle protein turnover between diseases/models (Fig. 1). Does this imply that various inflammatory diseases affect muscle protein metabolism differently? Not necessarily. A closer look at the clinical studies reveals some major differences in design and treatment that may have profound effects on muscle protein metabolism (Fig. 2).

Figure 2
Figure 2
Image Tools

A major difference is timing. Patients with severe burn injuries are usually studied after many days (>10) and the age of the patients is usually young. The majority of critical ill patients are studied between days 1 and 6 and are usually of older age. In the human model of sepsis, endotoxin injection, the first 4 h are investigated in young healthy individuals. The later the patients are studied during their disease progression, the larger the confounding influence from variables in addition to cytokines becomes. For example, immobility [43], nutritional status and feeding regime [44] all influence muscle protein turnover. Potentially more important is that the various cytokine concentrations change markedly over time and the changes are different between diseases and depending on the progression and severity of a disease. Moreover, the early proinflammatory phase (TNF-α, IL-1 and IL-6) is followed by a later anti-inflammatory cytokine phase [45]. Therefore, it is more likely that cytokines play a more prominent role in muscle loss in the initial proinflammatory phase of a disease.

Equation (Uncited)
Equation (Uncited)
Image Tools

The existing investigations provide little evidence that the best described cytokines, TNF-α and IL-6, directly regulate muscle protein metabolism but that does not exclude them from mediating important secondary effects that may cause muscle loss. Firstly, the acute decrease in blood amino acid levels seen with IL-6 infusion and endotoxin injection may decrease muscle protein turnover and contribute to an increase in net muscle protein proteolysis. Secondly, in severe illness the cytokines may be involved in the commonly seen acute hyperglycaemia/insulin resistance [46,47], potentially affecting both muscle protein synthesis and breakdown. Thirdly, cytokines stimulate the hypothalamic–pituitary–adrenal axis enhancing cortisol production that may enhance muscle protein breakdown. On the other hand, this normal corticosteroid response can also be impaired, adrenal insufficiency, when there is an extensive destruction of adrenal tissue or direct inhibition by cytokines together with tissue corticosteroid resistance [48]. This condition is treated with low doses of corticosteroids or corticosteroids are given in higher doses to suppress proinflammatory cytokines. These treatments may enhance muscle protein breakdown, even more so since immobility is reported to sensitize skeletal muscle to the catabolic effects of hypercortisolaemia [49]. Fourthly, the growth hormones–insulin growth factors (IGFs)/IGF-binding protein axis may be suppressed, associated with cytokine levels [50] and may work synergistically with catabolic hormones [51] in the (de)regulation of muscle protein balance. Fifthly, severe hypotension that can lead to shock is common in critically ill patients and characterized by disturbances of the macrocirculation and microcirculation associated with cytokines [52]. The impairment of the microcirculation is characterized by a decrease in the capillary densities [53] and blood flow in the remaining microvessels. Reduced blood flow in the muscle microvessels may compromise nutritional, that is, amino acids, and hormonal delivery to skeletal muscle, thereby affecting muscle protein metabolism and may also be the underlying cause of the insulin resistance towards muscle protein synthesis [40▪] in critical illness. Adrenergic agents are frequently required to correct the severe hypotension (dopamine, norepinephrine and epinephrine). These stress hormones as such may cause an increase in muscle protein breakdown, and as they exert peripheral vasoconstriction it may further exaggerate the microcirculatory disturbances. However, in contrast it has been shown that norepinephrine in severely hypotensive septic patients improved the muscle microcirculation possibly via the increased mean arterial blood pressure and systemic blood flow [54▪].

Equation (Uncited)
Equation (Uncited)
Image Tools
Back to Top | Article Outline

CONCLUSION

Equation (Uncited)
Equation (Uncited)
Image Tools

Recent studies suggest that the best described cytokines, TNF-α and IL-6, are unlikely to be the major direct mediators of muscle protein loss in inflammatory diseases. However, these cytokines can initiate important changes in secondary mediators and/or clinical complications that need correction therapies causing muscle wasting. Moreover, the general view from animal work is that in muscle wasting there are decreased rates of muscle protein synthesis and an increased rate of breakdown. However, this does not seem applicable for inflammatory diseases or human models of sepsis, in which the enhanced imbalance between these two processes is observed within an enhanced, normal or reduced muscle protein turnover.

Equation (Uncited)
Equation (Uncited)
Image Tools
Back to Top | Article Outline

Acknowledgements

The author would like to thank Dr Thomas Solomon for critically reviewing the manuscript.

Back to Top | Article Outline
Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 96).

Back to Top | Article Outline

REFERENCES

1. Lang CH, Frost RA. Sepsis-induced suppression of skeletal muscle translation initiation mediated by tumor necrosis factor [alpha]. Metabolism 2007; 56:49–57.

2. Vary TC. Acute oral leucine administration stimulates protein synthesis during chronic sepsis through enhanced association of eukaryotic initiation factor 4G with eukaryotic initiation factor 4E in rats. J Nutr 2007; 137:2074–2079.

3. Kazi AA, Pruznak AM, Frost RA, Lang CH. Sepsis-induced alterations in protein-protein interactions within mTOR complex 1 and the modulating effect of leucine on muscle protein synthesis. Shock 2011; 35:117–125.

4. Vary TC, Dardevet D, Grizard J, et al. Differential regulation of skeletal muscle protein turnover by insulin and IGF-I after bacteremia. Am J Physiol Endocrinol Metab 1998; 275:E584–E593.

5. Orellana RA, O’Connor PMJ, Nguyen HV, et al. Endotoxemia reduces skeletal muscle protein synthesis in neonates. Am J Physiol Endocrinol Metab 2002; 283:E909–E916.

6. Murton AJ, Alamdari N, Gardiner SM, et al. Effects of endotoxaemia on protein metabolism in rat fast-twitch skeletal muscle and myocardium. PLoS One 2009; 4:

7. Biolo G, Fleming RYD, Maggi SP, et al. Inverse regulation of protein turnover and amino acid transport in skeletal muscle of hypercatabolic patients. J Clin Endocrinol Metab 2002; 87:3378–3384.

8. Gore DC, Wolf SE, Sanford AP, et al. Extremity hyperinsulinemia stimulates muscle protein synthesis in severely injured patients. Am J Physiol Endocrinol Metab 2004; 286:E529–E534.

9. Tjäder I, Rooyackers O, Forsberg A-M, et al. Effects on skeletal muscle of intravenous glutamine supplementation to ICU patients. Intensive Care Med 2004; 30:266–275.

Klaude M, Mori M, Tjäder I, et al. Protein metabolism and gene expression in skeletal muscle of critically ill patients with sepsis. Clin Sci 2012; 122:133–142.

This is the first study providing detailed information on human muscle net proteolysis, protein synthesis and breakdown in critically ill patients with sepsis. Moreover, it includes measurements of gene expression and activities of enzymes involved in muscle protein breakdown pathways. Unfortunately, no information is provided on anabolic and catabolic hormones and cytokines.

11. Dworzak F, Ferrari P, Gavazzi C, et al. Effects of cachexia due to cancer on whole body and skeletal muscle protein turnover. Cancer 1998; 82:42–48.

12. Biolo G, De Cicco M, Dal Mas V, et al. Response of muscle protein and glutamine kinetics to branched-chain-enriched amino acids in intensive care patients after radical cancer surgery. Nutrition 2006; 22:475–482.

13. Dillon EL, Volpi E, Wolfe RR, et al. Amino acid metabolism and inflammatory burden in ovarian cancer patients undergoing intense oncological therapy. Clin Nutr 2007; 26:736–743.

14. Biolo G, De Cicco M, Lorenzon S, et al. Treating hyperglycemia improves skeletal muscle protein metabolism in cancer patients after major surgery. Crit Care Med 2008; 36:1768–1775.

15. Fong Y, Marano M, Moldawer L, et al. The acute splanchnic and peripheral tissue metabolic responses to endotoxin in humans. J Clin Invest 1990; 85:1896–1904.

16. 2005; Vesali RF, Klaude M, Rooyackers O, Wernerman J. 288:E360–E364.

Vesali RF, Cibicek N, Jakobsson T, et al. Protein metabolism in leg muscle following an endotoxin injection in healthy volunteers. Clin Sci 2010; 118:421–427.

This is the first study providing detailed information on human muscle net proteolysis, protein synthesis and breakdown in the human model of acute sepsis. They observed a decrease in muscle protein synthesis and breakdown, however, with an unchanged muscle net proteinbreakdown.

18. Li Y-P, Reid MB. NF-kappa B mediates the protein loss induced by TNF-alpha in differentiated skeletal muscle myotubes. Am J Physiol Regul Integr Comp Physiol 2000; 279:R1165–R1170.

19. Alvarez B, Quinn LS, Busquets S, et al. Tumor necrosis factor-[alpha] exerts interleukin-6-dependent and -independent effects on cultured skeletal muscle cells. Biochim Biophys Acta Mol Cell Res 2002; 1542:66–72.

20. Plaisance I, Morandi C, Murigande C, Brink M. TNF-{alpha} increases protein content in C2C12 and primary myotubes by enhancing protein translation via the TNF-R1, PI3K, and MEK. Am J Physiol Endocrinol Metab 2008; 294:E241–E250.

21. Williamson DL, Kimball SR, Jefferson LS. Acute treatment with TNF-{alpha} attenuates insulin-stimulated protein synthesis in cultures of C2C12 myotubes through a MEK1-sensitive mechanism. Am J Physiol Endocrinol Metab 2005; 289:E95–E104.

22. Los VT, Haagsman HP. TNF-[alpha] inhibits adult fast myosin accumulation in myotubes. Cytokine 2006; 35:154–158.

23. Zamir O, Hasselgren P, Kunkel S, et al. Evidence that tumor necrosis factor participates in the regulation of muscle proteolysis during sepsis. Arch Surg 1992; 127:170–174.

24. Goodman M. Tumor necrosis factor induces skeletal muscle protein breakdown in rats. Am J Physiol Endocrinol Metab 1991; 260:E727–E730.

25. Llovera M, Lopez-Soriano F, Argiles J. Effects of tumor necrosis factor-{alpha} on muscle-protein turnover in female wistar rats. J Natl Cancer Inst 1993; 85:1334–1339.

26. Hoshino E, Pichard C, Greenwood CE, et al. Body composition and metabolic rate in rat during a continuous infusion of cachectin. Am J Physiol Endocrinol Metab 1991; 260:E27–E36.

27. De Blaauw I, Eggermont A, Deutz N, et al. TNF-a; has no direct in vivo metabolic effect on human muscle. Int J Cancer 1997; 71:148–154.

28. Warren R, Starnes H, Gabrilove J, et al. The acute metabolic effects of tumor necrosis factor administration in humans. Arch Surg 1987; 122:1396–1400.

29. van Hall G, Steensberg A, Fischer C, et al. Interleukin-6 markedly decreases skeletal muscle protein turnover and increases nonmuscle amino acid utilization in healthy individuals. J Clin Endocrinol Metab 2008; 93:2851–2858.

30. Petersen AM, Plomgaard P, Fischer CP, et al. Acute moderate elevation of TNF-α does not affect systemic and skeletal muscle protein turnover in healthy humans. J Clin Endocrinol Metab 2009; 94:294–299.

31. Lang C, Frost R. Glucocorticoids and TNFa Interact cooperatively to mediate sepsis-induced leucine resistance in skeletal muscle. Mol Med 2006; 12:291–299.

32. Clark MA, Plank LD, Connolly AB, et al. Effect of a chimeric antibody to tumor necrosis factor-alpha on cytokine and physiologic responses in patients with severe sepsis – a randomized, clinical trial. Crit Care Med 1998; 26:1650–1659.

33. Metsios G, Stavropoulos-Kalinoglou A, Douglas K, et al. Blockade of tumour necrosis factor-{alpha} in rheumatoid arthritis: effects on components of rheumatoid cachexia. Rheumatology 2007; 46:1824–1827.

Toth MJ, LeWinter MM, Ades PA, Matthews DE. Impaired muscle protein anabolic response to insulin and amino acids in heart failure patients: relationship with markers of immune activation. Clin Sci 2010; 119:467–476.

This study provides detailed information on in-vivo muscle net proteolysis, protein synthesis and breakdown in chronic heart failure patients with low-grade inflammation. In adddition, it provides information and relations between muscle protein metabolism and inflammatory markers showing only a relation with IL-6 but not with TNF-α. Moreover, it provides evidence for anabolic resistant in these patients. During hyperinsulinaemia–hyperaminoacidaemia, muscle protein breakdown in the patients was less reduced as compared to healthy individuals. Of note is that the power of the study is low with only four patients of whom two had type 2 diabetes mellitus.

35. Goodman M. Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 1994; 205:182–185.

36. Williams A, Wang JJ, Wang L, et al. Sepsis in mice stimulates muscle proteolysis in the absence of IL-6. Am J Physiol Regul Integr Comp Physiol 1998; 275:R1983–R1991.

37. Llovera M, Carbó N, López-Soriano J, et al. Different cytokines modulate ubiquitin gene expression in rat skeletal muscle. Cancer Lett 1998; 133:83–87.

38. Tsujinaka T, Fujita J, Ebisui C, et al. Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice. J Clin Invest 1996; 97:244–249.

39. Baltgalvis K, Berger F, Peña M, et al. Muscle wasting and interleukin-6-induced atrogin-I expression in the cachectic mouse. Pflüg Archiv Eur J Physiol 2009; 457:989–1001.

Timmerman KL, Lee JL, Dreyer HC, et al. Insulin stimulates human skeletal muscle protein synthesis via an indirect mechanism involving endothelial-dependent vasodilation and mammalian target of rapamycin complex 1 signaling. J Clin Endocrinol Metab 2010; 95:3848–3857.

This study provides evidence that the increase in the muscle microcirculatory recruitement is involved in the insulin-mediated increase in muscle protein synthesis but does not affect the insulin-mediated decrease in muscle protein breakdown in healthy individuals. Similar mechanisms may play a role in critically ill patients who commonly have acute insulin resistance and severe hypotention-related disturbances in the muscle microcirculation.

41. Gore DC, Chinkes DL, Wolf SE, et al. Quantification of protein metabolism in vivo for skin, wound, and muscle in severe burn patients. JPEN J Parenter Enteral Nutr 2006; 30:331–338.

42. Gore DC, Wolfe RR, Chinkes DL. Quantification of amino acid transport through interstitial fluid: assessment of four-compartment modeling for muscle protein kinetics. Am J Physiol Endocrinol Metab 2007; 292:E319–E323.

43. Biolo G, Ciocchi B, Lebenstedt M, et al. Short-term bed rest impairs amino acid-induced protein anabolism in humans. J Physiol 2004; 558:381–388.

44. Fong Y, Marano M, Barber A, et al. Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in humans. Ann Surg 1989; 210:449–456.

45. Webster NR, Galley HF. Immunomodulation in the critically ill. Br J Anaesth 2009; 103:70–81.

46. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345:1359–1367.

47. Chen Q, Li N, Zhu W, et al. Insulin alleviates degradation of skeletal muscle protein by inhibiting the ubiquitin–proteasome system in septic rats. J Inflamm 2011; 8:13.

48. Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 2008; 36:1937–1949.

49. Ferrando A, Stuart C, Sheffield-Moore M, Wolfe R. Inactivity amplifies the catabolic response of skeletal muscle to cortisol. J Clin Endocrinol Metab 1999; 84:3515–3521.

50. Elijah IE, Branski LK, Finnerty CC, Herndon DN. The GH/IGF-1 system in critical illness. Best Pract Res Clin Endocrinol Metab 2011; 25:759–767.

51. Smith IJ, Alamdari N, O’Neal P, et al. Sepsis increases the expression and activity of the transcription factor Forkhead Box O 1 (FOXO1) in skeletal muscle by a glucocorticoid-dependent mechanism. Int J Biochem Cell Biol 2010; 42:701–711.

52. Hartemink KJ, Groeneveld ABJ. The hemodynamics of human septic shock relate to circulating innate immunity factors. Immunol Invest 2010; 39:849–862.

53. Ellis C, Jagger J, Sharpe M. The microcirculation as a functional system. Crit Care 2005; 9:S3–S8.

Georger J-F, Hamzaoui O, Chaari A, et al. Restoring arterial pressure with norepinephrine improves muscle tissue oxygenation assessed by near-infrared spectroscopy in severely hypotensive septic patients. Intensive Care Med 2010; 36:1882–1889.

This article provides information that the microcirculation in skeletal muscle may be improved by norephinephrine, restoring mean arterial blood pressure in hypotensive septic patients which may potentially improve the net muscle protein balance.

Keywords:

amino acids; critical illness; endotoxin; IL-6; muscle breakdown; muscle synthesis; proteolysis; sepsis; TNF-α

© 2012 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.